EP1989214B1 - Procede de preparation d'un agoniste de recepteur a2a-adenosine et ses polymorphes - Google Patents
Procede de preparation d'un agoniste de recepteur a2a-adenosine et ses polymorphes Download PDFInfo
- Publication number
- EP1989214B1 EP1989214B1 EP07763545.6A EP07763545A EP1989214B1 EP 1989214 B1 EP1989214 B1 EP 1989214B1 EP 07763545 A EP07763545 A EP 07763545A EP 1989214 B1 EP1989214 B1 EP 1989214B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- hydroxymethyl
- oxolan
- dihydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229940122614 Adenosine receptor agonist Drugs 0.000 title description 5
- 239000003379 purinergic P1 receptor agonist Substances 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 title description 2
- 101150051188 Adora2a gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 27
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 17
- LZPZPHGJDAGEJZ-AKAIJSEGSA-N regadenoson Chemical compound C1=C(C(=O)NC)C=NN1C1=NC(N)=C(N=CN2[C@H]3[C@@H]([C@H](O)[C@@H](CO)O3)O)C2=N1 LZPZPHGJDAGEJZ-AKAIJSEGSA-N 0.000 claims description 14
- HMFLBGNCDZYITR-UHFFFAOYSA-N ethyl 2-formyl-3-oxopropanoate Chemical compound CCOC(=O)C(C=O)C=O HMFLBGNCDZYITR-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 150000004682 monohydrates Chemical class 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 239000002002 slurry Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- -1 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl Chemical group 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 23
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 238000004458 analytical method Methods 0.000 description 14
- 238000001228 spectrum Methods 0.000 description 12
- BAYFDGKAUSOEIS-UUOKFMHZSA-N (2r,3r,4s,5r)-2-(6-amino-2-hydrazinylpurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C12=NC(NN)=NC(N)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O BAYFDGKAUSOEIS-UUOKFMHZSA-N 0.000 description 10
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 239000012467 final product Substances 0.000 description 6
- CDQVVPUXSPZONN-WPPLYIOHSA-N 1-[6-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl]-n-methylpyrazole-4-carboxamide;hydrate Chemical compound O.C1=C(C(=O)NC)C=NN1C1=NC(N)=C(N=CN2[C@H]3[C@@H]([C@H](O)[C@@H](CO)O3)O)C2=N1 CDQVVPUXSPZONN-WPPLYIOHSA-N 0.000 description 5
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 5
- 229960005305 adenosine Drugs 0.000 description 5
- ZPVLTIXYQGANFL-IDTAVKCVSA-N ethyl 1-[6-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl]pyrazole-4-carboxylate Chemical compound C1=C(C(=O)OCC)C=NN1C1=NC(N)=C(N=CN2[C@H]3[C@@H]([C@H](O)[C@@H](CO)O3)O)C2=N1 ZPVLTIXYQGANFL-IDTAVKCVSA-N 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000003586 protic polar solvent Substances 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- BIXYYZIIJIXVFW-UUOKFMHZSA-N (2R,3R,4S,5R)-2-(6-amino-2-chloro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O BIXYYZIIJIXVFW-UUOKFMHZSA-N 0.000 description 3
- 0 *c1nc(N)c2nc[n]([C@@]([C@@]3O)O[C@@](CO)[C@@]3O)c2n1 Chemical compound *c1nc(N)c2nc[n]([C@@]([C@@]3O)O[C@@](CO)[C@@]3O)c2n1 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 150000001344 alkene derivatives Chemical class 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- SIALOQYKFQEKOG-UHFFFAOYSA-N ethyl 3,3-diethoxypropanoate Chemical compound CCOC(OCC)CC(=O)OCC SIALOQYKFQEKOG-UHFFFAOYSA-N 0.000 description 3
- SIZVDXCOFBYELW-QGOBPSGUSA-N ethyl 5-[9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-[[(e)-3-ethoxy-2-formyl-3-oxoprop-1-enyl]amino]purin-2-yl]-1h-pyrazole-4-carboxylate Chemical compound C1=NC=2C(N/C=C(\C=O)C(=O)OCC)=NC(C=3C(=CNN=3)C(=O)OCC)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O SIZVDXCOFBYELW-QGOBPSGUSA-N 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 102000009346 Adenosine receptors Human genes 0.000 description 2
- 108050000203 Adenosine receptors Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 239000003218 coronary vasodilator agent Substances 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000002076 thermal analysis method Methods 0.000 description 2
- 230000024883 vasodilation Effects 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920003350 Spectratech® Polymers 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 238000004164 analytical calibration Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- SIZVDXCOFBYELW-WCJVWAGYSA-N ethyl 5-[9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-[[(z)-3-ethoxy-2-formyl-3-oxoprop-1-enyl]amino]purin-2-yl]-1h-pyrazole-4-carboxylate Chemical compound C1=NC=2C(N\C=C(\C=O)C(=O)OCC)=NC(C=3C(=CNN=3)C(=O)OCC)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O SIZVDXCOFBYELW-WCJVWAGYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000005338 frosted glass Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000011045 prefiltration Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000007430 reference method Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000002336 sorption--desorption measurement Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- BKVIYDNLLOSFOA-OIOBTWANSA-N thallium-201 Chemical compound [201Tl] BKVIYDNLLOSFOA-OIOBTWANSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- GZXOHHPYODFEGO-UHFFFAOYSA-N triglycine sulfate Chemical class NCC(O)=O.NCC(O)=O.NCC(O)=O.OS(O)(=O)=O GZXOHHPYODFEGO-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Claims (11)
- Procédé pour la préparation à grande échelle de (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxyméthyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-méthylcarboxamide:
la mise en contact d'un composé de la formule (4):
- Procédé selon la revendication 1, dans laquelle le composé de la formule (4) est mis à réagir avec une solution aqueuse de méthylamine à une température initiale d'environ 0-5°C suivi par un réchauffement à environ 50-70°C.
- Procédé selon la revendication 1, dans laquelle la réaction est menée dans un réacteur sous pression scellé.
- Procédé selon l'une quelconque des revendications 1 à 3, dans laquelle le produit final (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxyméthyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-méthylcarboxamide est isolé sous forme du monohydrate pur par:(a) la dissolution du produit dans un solvant,(b) l'ajout d'eau purifiée,(c) la filtration de la suspension épaisse ainsi formée,(d) le lavage des contenus du filtre avec de l'eau suivie par de l'éthanol, et(e) le séchage du solide qui reste sous vide à une température qui ne dépasse pas 40°C.
- Procédé selon la revendication 4, dans laquelle le solvant utilisé dans l'étape (a) est le diméthylsulfoxyde.
- Procédé selon l'une quelconque des revendications 1 à 5, où le procédé comprend en outre la synthèse du composé de la formule (4):
- Procédé selon la revendication 6, dans laquelle la réaction est menée dans de l'éthanol.
- Procédé selon la revendication 7, dans laquelle la réaction a lieu à une température d'environ 80°C.
- Procédé selon l'une quelconque des revendications 6 à 8, dans laquelle il est utilisé environ 2-10 fois d'excès molaire de 2-formyl-3-oxopropionate d'éthyle.
- Procédé selon la revendication 9, dans laquelle il est utilisé environ 5-10 fois d'excès molaire de 2-formyl-3-oxopropionate d'éthyle.
- Procédé selon l'une quelconque des revendications 6 à 10, comprenant en outre l'étape (v):préparation du composé de la formule (2):comprenant:
la réaction d'un composé de la formule (1):
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI200731820A SI1989214T1 (sl) | 2006-02-03 | 2007-02-02 | Postopek za pripravo A2A-adenozin receptor agonista in njegovih polimorfov |
| EP12008201.1A EP2581381A3 (fr) | 2006-02-03 | 2007-02-02 | Procédé de préparation d'un agoniste du récepteur A2A-adénosine et ses polymorphes |
| PL07763545T PL1989214T3 (pl) | 2006-02-03 | 2007-02-02 | Proces otrzymywania agonisty receptora adenozynowego a2a i jego polimorfów |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US76511406P | 2006-02-03 | 2006-02-03 | |
| US80185706P | 2006-05-18 | 2006-05-18 | |
| PCT/US2007/003022 WO2007092372A1 (fr) | 2006-02-03 | 2007-02-02 | Procede de preparation d'un agoniste de recepteur a2a-adenosine et ses polymorphes |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP12008201.1A Division-Into EP2581381A3 (fr) | 2006-02-03 | 2007-02-02 | Procédé de préparation d'un agoniste du récepteur A2A-adénosine et ses polymorphes |
Publications (3)
| Publication Number | Publication Date |
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| EP1989214A1 EP1989214A1 (fr) | 2008-11-12 |
| EP1989214B1 true EP1989214B1 (fr) | 2016-06-22 |
| EP1989214B8 EP1989214B8 (fr) | 2016-12-21 |
Family
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| Application Number | Title | Priority Date | Filing Date |
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| EP07763545.6A Active EP1989214B8 (fr) | 2006-02-03 | 2007-02-02 | Procede de preparation d'un agoniste de recepteur a2a-adenosine et ses polymorphes |
| EP12008201.1A Withdrawn EP2581381A3 (fr) | 2006-02-03 | 2007-02-02 | Procédé de préparation d'un agoniste du récepteur A2A-adénosine et ses polymorphes |
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| EP12008201.1A Withdrawn EP2581381A3 (fr) | 2006-02-03 | 2007-02-02 | Procédé de préparation d'un agoniste du récepteur A2A-adénosine et ses polymorphes |
Country Status (18)
| Country | Link |
|---|---|
| US (8) | US7732595B2 (fr) |
| EP (2) | EP1989214B8 (fr) |
| JP (3) | JP5326156B2 (fr) |
| KR (2) | KR20080090491A (fr) |
| CN (1) | CN102260311A (fr) |
| AU (1) | AU2007212542B2 (fr) |
| CA (1) | CA2640089C (fr) |
| ES (1) | ES2593028T3 (fr) |
| HK (1) | HK1127358A1 (fr) |
| IL (2) | IL193153A (fr) |
| MX (1) | MX2010014060A (fr) |
| NO (1) | NO341322B1 (fr) |
| NZ (1) | NZ570239A (fr) |
| PL (1) | PL1989214T3 (fr) |
| PT (1) | PT1989214T (fr) |
| RU (1) | RU2447081C2 (fr) |
| SI (1) | SI1989214T1 (fr) |
| WO (1) | WO2007092372A1 (fr) |
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- 2007-02-02 PL PL07763545T patent/PL1989214T3/pl unknown
- 2007-02-02 EP EP07763545.6A patent/EP1989214B8/fr active Active
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